Safety and efficacy of magnesium-rich artificial cerebrospinal fluid for subarachnoid hemorrhage.

Objectives: This study aimed to investigate the efficacy of using a newly formulated magnesium-rich artificial cerebrospinal fluid (MACSF) as an alternative to normal saline (NS) for intraoperative irrigation during aneurysm clipping in improving the prognosis of patients with Aneurysmal subarachnoid hemorrhage (aSAH). Methods: Patients with aSAH who underwent intraoperative irrigation with MACSF or NS during the clipping in the First Affiliated Hospital of Xi 'an Jiaotong University from March 2019 to March 2022 were selected as MACSF group and NS group, respectively. The primary prognostic indicators were the incidence of favorable outcomes (mRS 0-2). The secondary outcome measures included cerebral vasospasm (CVS), mortality, total hospital stay, and intensive care unit (ICU) stay. Safety was evaluated based on the occurrence rates of hypermagnesemia, meningitis, and hydrocephalus. Results: Overall, 34 and 37 patients were enrolled in the MACSF and NS groups, respectively. At 90 days after aSAH onset, the proportion of favorable prognosis in the MACSF group was significantly higher than that in the NS group (p = 0.035). The incidence of CVS within 14 days after surgery was significantly lower in the MACSF group than that in the NS group (p = 0.026). The mortality rate in the MACSF group was significantly lower than in the NS group (p = 0.048). The median lengths of hospital stay (p = 0.008) and ICU stay (p = 0.018) were significantly shorter in the MACSF group than in the NS group. No significant differences were observed in safety measures. Conclusion: Using MACSF as an irrigation fluid for aneurysm clipping can significantly improve the 90-day prognosis of patients with aSAH, which may be related to the reduced incidence of CVS. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT04358445.

Development of prognostic indicator based on NAD+ metabolism related genes in glioma.

Background: Studies have shown that Nicotinamide adenine dinucleotide (NAD+) metabolism can promote the occurrence and development of glioma. However, the specific effects and mechanisms of NAD+ metabolism in glioma are unclear and there were no systematic researches about NAD+ metabolism related genes to predict the survival of patients with glioma. Methods: The research was performed based on expression data of glioma cases in the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Firstly, TCGA-glioma cases were classified into different subtypes based on 49 NAD+ metabolism-related genes (NMRGs) by consensus clustering. NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were gotten by intersecting the 49 NMRGs and differentially expressed genes (DEGs) between normal and glioma samples. Then a risk model was built by Cox analysis and the least shrinkage and selection operator (LASSO) regression analysis. The validity of the model was verified by survival curves and receiver operating characteristic (ROC) curves. In addition, independent prognostic analysis of the risk model was performed by Cox analysis. Then, we also identified different immune cells, HLA family genes and immune checkpoints between high and low risk groups. Finally, the functions of model genes at single-cell level were also explored. Results: Consensus clustering classified glioma patients into two subtypes, and the overall survival (OS) of the two subtypes differed. A total of 11 NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were screened by overlapping 5,995 differentially expressed genes (DEGs) and 49 NAD+ metabolism-related genes (NMRGs). Next, four model genes, PARP9, BST1, NMNAT2, and CD38, were obtained by Cox regression and least absolute shrinkage and selection operator (Lasso) regression analyses and to construct a risk model. The OS of high-risk group was lower. And the area under curves (AUCs) of Receiver operating characteristic (ROC) curves were >0.7 at 1, 3, and 5 years. Cox analysis showed that age, grade G3, grade G4, IDH status, ATRX status, BCR status, and risk Scores were reliable independent prognostic factors. In addition, three different immune cells, Mast cells activated, NK cells activated and B cells naive, 24 different HLA family genes, such as HLA-DPA1 and HLA-H, and 8 different immune checkpoints, such as ICOS, LAG3, and CD274, were found between the high and low risk groups. The model genes were significantly relevant with proliferation, cell differentiation, and apoptosis. Conclusion: The four genes, PARP9, BST1, NMNAT2, and CD38, might be important molecular biomarkers and therapeutic targets for glioma patients.

A Novel Multi-Omics Analysis Model for Diagnosis and Survival Prediction of Lower-Grade Glioma Patients.

Background: Lower-grade gliomas (LGGs) are characterized by remarkable genetic heterogeneity and different clinical outcomes. Classification of LGGs is improved by the development of molecular stratification markers including IDH mutation and 1p/19q chromosomal integrity, which are used as a hallmark of survival and therapy sensitivity of LGG patients. However, the reproducibility and sensitivity of the current classification remain ambiguous. This study aimed to construct more accurate risk-stratification approaches. Methods: According to bioinformatics, the sequencing profiles of methylation and transcription and imaging data derived from LGG patients were analyzed and developed predictable risk score and radiomics score. Moreover, the performance of predictable models was further validated. Results: In this study, we determined a cluster of 6 genes that were correlated with IDH mutation/1p19q co-deletion status. Risk score model was calculated based on 6 genes and showed gratifying sensitivity and specificity for survival prediction and therapy response of LGG patients. Furthermore, a radiomics risk score model was established to noninvasively assist judgment of risk score in pre-surgery. Taken together, a predictable nomogram that combined transcriptional signatures and clinical characteristics was established and validated to be preferable to the histopathological classification. Our novel multi-omics nomograms showed a satisfying performance. To establish a user-friendly application, the nomogram was further developed into a web-based platform: https://drw576223193.shinyapps.io/Nomo/, which could be used as a supporting method in addition to the current histopathological-based classification of gliomas. Conclusions: Our novel multi-omics nomograms showed the satisfying performance of LGG patients and assisted clinicians to draw up individualized clinical management.

CRB2 enhances malignancy of glioblastoma via activation of the NF-κB pathway.

Glioblastoma (GBM) is one of the most lethal types of primary brain tumors in adults with a median survival of less than 15 months. Although comprehensive clinical treatment strategies including surgical resection followed by radiotherapy and chemotherapy are widely applied, the prognosis for GBM patients remains dismal. The Nuclear Factor-κB (NF-κB) signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation, and aberrant activation of NF-κB signaling has been implicated in the propagation of a wide range of cancers. However, the underlying mechanism of NF-κB activation still requires further investigation. Here, we report that crumbs homolog 2 (CRB2) is markedly up-regulated in human GBM relative to non-tumor tissues or normal astrocytes. Clinically, enriched CRB2 could be observed in high grade glioma with IDH IDH wild-type and 1p19q co-deletion and implied poor outcome in GBM. Consistent with this, malignant characteristics of GBM cells including proliferation, migration, invasion and tumorigenesis were significantly suppressed by lentivirus knock-down of CRB2. Furthermore, exogenous overexpression of CRB2 enhanced the malignant biological signatures of GBM cells as well as therapy resistance to temozolomide (TMZ). To further investigate the molecular mechanisms responsible, bioinformatics analysis was performed using 3 public databases, with the result that CRB2 was found to correlate closely with tumor necrosis factor α (TNFα)-NF-κB signaling. Mechanistically, elevated CRB2 increased the phosphorylation of IκB-kinase α (IKKα), thus activating NF-κB via reduction of Ikß protein. Taken together, these data suggest that CRB2 might be a reliable prognostic biomarker and potential therapeutic target for GBM.

NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway.

Glioblastoma (GBM) is one of the most lethal primary brain tumor with a poor median survival less than 15 months. Despite the development of the clinical strategies over the decades, the outcomes for GBM patients remain dismal due to the strong proliferation and invasion ability and the acquired resistance to radiotherapy and chemotherapy. Therefore, developing new biomarkers and therapeutic strategies targeting GBM is in urgent need. In this study, gene expression datasets and relevant clinical information were extracted from public cancers/glioma datasets, including TCGA, GRAVENDEEL, REMBRANDT, and GILL datasets. Differentially expressed genes were analyzed and NEK2 was picked as a candidate gene for subsequent validation. Human tissue samples and corresponding data were collected from our center and detected by immunohistochemistry analysis. Molecular biological assays and in vivo xenograft transplantation were performed to confirm the bioinformatic findings. High-throughput RNA sequencing, followed by KEGG analysis, GSEA analysis and GO analysis were conducted to identify potential signaling pathways related to NEK2 expression. Subsequent mechanism assays were used to verify the relationship between NEK2 and NF-κB signaling. Overall, we identified that NEK2 is significantly upregulated in GBM and the higher expression of NEK2 exhibited a poorer prognosis. Functionally, NEK2 knockdown attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM while NEK2 overexpression promoted the GBM progression. Furthermore, High-throughput RNA sequencing and bioinformatics analysis indicated that NEK2 was positively related to the NF-κB signaling pathway in GBM. Mechanically, NEK2 activated the noncanonical NF-κB signaling pathway by phosphorylating NIK and increasing the activity and stability of NIK. In conclusion, NEK2 promoted the progression of GBM through activation of noncanonical NF-κB signaling, indicating that NEK2- NF-κB axis could be a potential drug target for GBM.

Retinol binding protein 1-dependent activation of NF- κB signaling enhances the malignancy of non-glioblastomatous diffuse gliomas.

Nonglioblastomatous diffuse glioma (non-GDG) is a heterogeneous neuroepithelial tumor that exhibits a varied survival range from 4 to 13 years based on the diverse subtypes. Recent studies demonstrated novel molecular markers can predict prognosis for non-GDG patients; however, these findings as well as pathological classification strategies show obvious limitations on malignant transition due to the heterogeneity among non-GDGs. Therefore, developing reliable prognostic biomarkers and therapeutic targets have become an urgent need for precisely distinguishing non-GDG subtypes, illuminating the underlying mechanism. Nuclear factor κß (NF-κB) has been proved to be a significant nuclear transcriptional regulator with specific DNA-binding sequences to participate in multiple pathophysiological processes. However, the underlying mechanism of NF-κB activation still needs to be further investigated. Herein, our results indicated retinol-binding protein 1 (RBP1) was significantly upregulated in the IDHWT and 1p19qNon co-del non-GDG subtypes and enriched RBP1 expression was markedly correlated with more severe outcomes. Additionally, malignant signatures of the non-GDG cells including proliferation, migration, invasion, and self-renewal were significantly suppressed by lentiviral knockdown of RBP1. To further explore the underlying molecular mechanism, bioinformatics analysis was performed using databases, and the results demonstrated RBP1 was strongly correlated with tumor necrosis factor α (TNFα)-NF-κB signaling. Moreover, exogenous silencing of RBP1 reduced phosphorylation of IkB-kinase α (IKKα) and thus decreased NF-κB expression via decreasing the degradation of the IκBα protein. Altogether, these data suggested RBP1-dependent activation of NF-κB signaling promoted malignancy of non-GDG, indicating that RBP1 could be a reliable prognostic biomarker and potential therapeutic target for non-GDG.

FABP5 enhances malignancies of lower-grade gliomas via canonical activation of NF-κB signaling.

Low-grade gliomas (LGGs) are grade III gliomas based on the WHO classification with significant genetic heterogeneity and clinical properties. Traditional histological classification of gliomas has been challenged by the improvement of molecular stratification; however, the reproducibility and diagnostic accuracy of LGGs classification still remain poor. Herein, we identified fatty acid binding protein 5 (FABP5) as one of the most enriched genes in malignant LGGs and elevated FABP5 revealed severe outcomes in LGGs. Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, immigration, invasion and TMZ resistance, contrarily, the malignancies of LGGs were enhanced by exogenous overexpression of FABP5. Mechanistically, epithelial-mesenchymal transition (EMT) was correlated to FABP5 expression in LGGs and tumour necrosis factor α (TNFα)-dependent NF-κB signalling was involved in this process. Furthermore, FABP5 induced phosphorylation of inhibitor of nuclear factor kappa-B kinase α (IKKα) thus activated nuclear factor kappa-B (NF-κB) signalling. Taken together, our study indicated that FABP5 enhances malignancies of LGGs through canonical activation of NF-κB signalling, which could be used as individualized prognostic biomarker and potential therapeutic target of LGGs.

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling.

BACKGROUND: Glioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. METHODS: Transcriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. RESULTS: In this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1. CONCLUSION: Loss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling.

BACKGROUND: Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. Circular RNAs (circRNAs) have been reported to play vital roles in progression of cancer including glioma, and circKIF4A is up-regulated in glioma tissues. However, its role and mechanisms in gliomas are unclear. METHODS: circKIF4A and miR-139-3p were determined by qRT-PCR. Transwell assay, wound-healing assay, cell colony formation and flow cytometry were performed to measure cell invasion, migration, proliferation and apoptosis. Western blotting was used to evaluate Wnt/ß-catenin pathway-related protein. Luciferase reporter assays confirmed the relationship among circKIF4A, miR-139-3p and Wnt5a. Sphere formation was performed to measure the ability of glioma-initiating cells (GICs) spheroid formation. A nude mouse xenograft model was established and immunohistochemical staining was used to detect Ki-67 and Wnt5a levels. RESULTS: circKIF4A and Wnt5a were up-regulated and miR-139-3p was down-regulated in both glioma cells and tissues. circKIF4A promoted Wnt5a expression by sponging miR-139-3p. Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p. Knockdown of circKIF4A inhibited Wnt/ß-catenin signaling pathway and proliferation-related signal via miR-139-3p. Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/ß-catenin signaling pathway and proliferation-related signal in GICs. Additionally, depletion of circKIF4A decreased the expression level of Wnt5a and Ki-67, inhibited tumorigenesis in xenograft modes. CONCLUSION: circKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis. The results indicated that circKIF4A may be a potential target for clinical treatment of glioma.

Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is identified as a lethal malignant tumor derived from the nervous system. Despite the standard clinical strategy including maximum surgical resection, temozolomide (TMZ) chemotherapy, and radiotherapy, the median survival of GBM patients remains <15 months. Accumulating evidence indicates that rapid-acquired radioresistance is one of the most common reasons for GBM recurrence. Therefore, developing novel therapeutic targets for radioresistant GBM could yield long-term cures. AIMS: To investigate the functional role of CXCL1 in the acquired radioresistance and identify the molecular pathway correlated to CXCL1. RESULTS: In this study, we identified that CXCL1 is highly expressed in GBM and the elevation of CXCL1 is involved in radioresistance and poor prognosis in GBM patients. Additionally, silencing CXCL1 attenuated the proliferation and radioresistance of GBM cells. Furthermore, we demonstrated that CXCL1-overexpression induced radioresistance through mesenchymal transition of GBM via the activation of nuclear factor-kappa B (NF-κB) signaling. CONCLUSION: CXCL1 was highly enriched in GBM and positively correlated with poor prognosis in GBM patients. Additionally, elevated CXCL1 induced radioresistance in GBM through regulation of NF-κB signaling by promoting mesenchymal transition in GBM.

Retraction: Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma.

Retraction: Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma, CNS Neuroscience & Therapeutics 2019, (https://doi.org/10.1111/cns.13227). The above article published online on 02 October 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief Jun Chen, and John Wiley & Sons Ltd. The retraction has been agreed due to unreliable data and consequently its misleading results and conclusions.

Polo­like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma.

Glioblastoma (GBM) is one of the most malignant tumors in adults, associated with severe outcomes (median survival, <2 years). Multiple mechanisms are known to be involved in tumor recurrence and treatment resistance in GBM, however, the key regulator for GBM tumorigenesis and therapy resistance remains unclear. To clarify a novel potential functional mechanism of GBM recurrence, a wide range of experiments including in vitro molecular biological experiments and in vivo intracranial xenograft tumor models were performed in the present study. With bioinformatics analysis, polo­like kinase 4 (PLK4) was initially identified as one of the most upregulated kinase encoding genes in GBM, which was functionally required for both in vitro cell proliferation and in vivo tumorigenesis in GBM. Clinically, an elevated PLK4 expression was observed in high grade glioma patients, which was associated with poor prognosis. In addition, PLK4 enhanced radioresistance in GBM, while PLK4 knockdown via lentivirus transfection significantly increased the radiosensitivity of GBM cells. Mechanically, PLK4 expression was markedly elevated by the exogenous overexpression of ATPase family AAA domain­containing protein 2 (ATAD2) in GBM cells. Collectively, the results suggested that the ATAD2­dependent transcriptional regulation of PLK4 promoted cell proliferation and tumorigenesis, as well as radioresistance in GBM, thus potentially inducing tumor recurrence. PLK4 could therefore serve as a potential therapeutic target for GBM treatment.

Inflammatory biomarkers in prognostic analysis for patients with glioma and the establishment of a nomogram.

Being biomarkers that reflect host nutritional and immune status, prognostic nutritional index (PNI) and neutrophil/lymphocyte ratio (NLR) have been identified to be independent prognostic factors in various malignancies. The aim of the present study was to determine the predictive value of these parameters for the prognosis of patients with glioma. Hematological and clinicopathological data were retrospectively analyzed from 128 patients with glioma who underwent brain tumor resection between January 2008 and December 2012. Receiver operating characteristic (ROC) analysis was used to determine the optimal cut-offs for PNI and NLR. Kaplan-Meier survival analysis, and univariate and multivariate analyses based on Cox proportional hazards regression model were used to determine whether NLR and PNI were associated with the prognosis of patients with glioma. R software was used to develop nomograms with all the independent prognostic factors included. Kaplan-Meier analysis followed by log-rank tests indicated that NLR ≥2.8 and PNI <45 were significantly associated with decreased overall survival time. The subsequent multivariate analysis indicated that age ≥50 years [hazard ratio (HR), 2.328; 95% confidence interval (CI), 1.386-3.908; P<0.001], high-grade glioma (HR, 3.088; 95% CI, 1.893-5.037; P<0.001), gross total resection (HR, 0.606; 95% CI, 0.380-0.965; P=0.035) and NLR ≥2.8 (HR, 2.037; 95% CI, 1.264-3.281; P=0.003) were independent prognostic factors. The results of the present study indicated that high NLR was an independent risk factor for overall survival rates in patients with glioma, which indicated its value in improving the current prognostic model.

Targeting dual specificity protein kinase TTK attenuates tumorigenesis of glioblastoma.

Accumulating evidence has proved that glioma stem-like cells (GSCs) are responsible for tumorigenesis, treatment resistance, and subsequent tumor recurrence in glioblastoma (GBM). In this study, we identified dual specificity protein kinase TTK (TTK) as the most up-regulated and differentially expressed kinase encoding genes in GSCs. Functionally, TTK was essential for in vitro clonogenicity and in vivo tumor propagation in GSCs. Clinically, TTK expression was highly enriched in GBM, moreover, was inversely correlated with a poor prognosis in GBM patients. Mechanistically, mitochondrial fission regulator 2 (MTFR2) was identified as one of the most correlated genes to TTK and transcriptionally regulated TTK expression via activation of TTK promoter. Collectively, MTFR2-dependent regulation of TTK plays a key role in maintaining GSCs in GBM and is a potential novel druggable target for GBM.

Serine/Threonine Kinase CHEK1-Dependent Transcriptional Regulation of RAD54L Promotes Proliferation and Radio Resistance in Glioblastoma.

Accumulating evidence indicates that Checkpoint kinase 1 (CHEK1) plays an essential role in tumor cells and that it could induce cell proliferation and could be related to prognosis in multiple types of cancer. However, the biological role and molecular mechanism of CHEK1 in GBM still remain unclear. In this study, we identified that CHEK1 expression was enriched in glioblastoma (GBM) tumors and was functionally required for tumor proliferation and that its expression was associated to poor prognosis in GBM patients. Mechanically, CHEK1 induced radio resistance in GBM cells, and CHEK1 knockdown increased cell apoptosis when combined with radiotherapy via regulation of the DNA repair/recombination protein 54L (RAD54L) expression. Therapeutically, we found that CHEK1 inhibitor attenuated tumor growth both in vitro and in vivo. Collectively, CHEK1 promotes proliferation, induces radio resistance in GBM, and could become a potential therapeutic target for GBM.

Betulinic acid derivative B10 inhibits glioma cell proliferation through suppression of SIRT1, acetylation of FOXO3a and upregulation of Bim/PUMA.

Glioma is the most common primary malignant tumor of the central nervous system. B10 is a new glycosylated derivative of betulinic acid with enhanced cytotoxic activity. The present study was designed to explore the molecular mechanism underlying the anticancer effect of B10 in glioma cells. 25-50µM B10 resulted in a significant decrease of cell viability and BrdU incorporation. 25-50mg/kg B10 significantly reduced the implanted tumor weight and volume in nude mice. Activation of apoptosis was found in glioma cells when the cells were exposed to B10, as evidenced by increased number of TUNEL-stained cells, increased caspase 3 and 9 activities, and Bax and cleaved PARP expression. B10 caused a significant decrease in mitochondrial oxygen consumption rate, mitochondrial complex I, II, III, IV, and V activities, and ATP level, and increase of mitochondrial ROS production, indicating the induction of mitochondrial dysfunction. B10 reduced the expression of sirtuin (SIRT) 1 and resulted in an increase in forkhead box O (FOXO) 3a expression and acetylation. Activation of SIRT1 by SRT-1720 and downregualtion of FOXO3a using shRNA significantly inhibited B10-induced cytotoxicity. B10 markedly increased the expression of Bim and PUMA. Downregualtion of FOXO3a or activation of SIRT1 significantly inhibited B10-induced increase of Bim and PUMA expression. Downregualtion of Bim or PUMA could suppress B10-induced increase of Bax expression. Moreover, B10-induced cytotoxicity was significantly suppressed by downregulation of Bim or PUMA. In summary, we identified B10 as a potent therapeutic candidate for glioma treatment and SIRT1-FOXO3a-Bim/PUMA axis as a novel therapeutic target.

MicroRNA-206 Inhibited the Progression of Glioblastoma Through BCL-2.

Gliomas are the most common type of brain tumor and have a poor prognosis. MicroRNAs (miRNAs) are a class of small, endogenous, and non-coding RNAs that play crucial roles in cell proliferation, survival, and invasion. Deregulated expression of miR-206 has been investigated in many cancers. However, the role of miR-206 in glioblastoma is still unclear. In the present study, we found that the expression of miR-206 was decreased in cancer tissues compared with normal tissues. However, the expression level of BCL-2 was higher in cancer tissues than that in normal tissues (all p < 0.001). Statistically, the expression level of BCL-2 was inversely correlated with the miR-206. In addition, the overall survival of glioblastoma patients with lower miR-206 expression was significantly shorter than those with high miR-206 expression (p < 0.001). Besides, the expression of miR-206 was also decreased in U87 and U251 cells. In vitro assays showed that ectopic miR-206 expression affected the proliferation, cell cycle, and invasion in U87 and U251 cells. Importantly, we identified BCL-2 as a direct target of miR-206 in U87 and U251 cells using luciferase assay. Overexpression of BCL-2 partially attenuated the miR-206-mediated cell proliferation. In vivo, overexpression of miR-206 suppressed the progression of glioblastoma cells using mice xenograft model. In conclusion, this study suggested that miR-206 could act as a tumor suppressor gene through inhibiting BCL-2 in the development of glioblastoma.

DNA repair gene XRCC3 Thr241Met polymorphism and susceptibility to glioma: A case-control study.

The DNA repair gene, X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism may be associated with a susceptibility to glioma. The present study aimed to investigate the association between the XRCC3 Thr241Met polymorphism and the potential susceptibility to gliomas. A hospital-based case-control study was conducted, which included a total of 886 patients with glioma and 886 healthy control subjects. Peripheral blood samples were extracted and the polymerase chain reaction-restriction fragment length polymorphism method was performed to analyze the genotypes. The glioma patients had a significantly higher frequency of the XRCC3 241 MetMet genotype [odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.09-2.41; P=0.02] compared with the control subjects. When stratified by the grade of the glioma, the patients with stage IV glioma (according to the World Health Organization classification) had a significantly higher frequency of the XRCC3 241 MetMet genotype (OR=1.61; 95% CI: 1.06-2.44; P=0.03). When stratified by the histology of the glioma, there was no significant difference in the distribution of each genotype. The findings of the present study indicate that the XRCC3 Thr241Met polymorphism is associated with a susceptibility to glioma.

Pressing the nerve alters muscle fiber types of the peroneus longus in rats: preliminary evidence for external anal sphincteroplasty.

BACKGROUND: Studies have demonstrated that anal reconstruction with a gracilis graft pressing the dominant nerve could be used to treat fecal incontinence. However, the detailed mechanism by this remains unknown. Herein, we evaluated the alteration in muscle fiber types and contractility of the peroneus longus muscle in rats after pressing its dominant nerves. MATERIAL AND METHODS: The rat soleus and peroneus longus were exposed during surgery. The superficial peroneal nerve was pressed so that the peroneus longus temporarily lost its innervation. The epimysium between the soleus and the peroneus longus was removed. The end point of the soleus was cut off and the epimysium of the contact surfaces of the soleus and the peroneus longus were sutured. Five months later, peroneus longus contractility was recorded by the myograph system, and types of muscle fibers were observed using the myosin ATPase staining method. RESULTS: The skeletal muscle fiber type underwent adaptive changes due to double innervations with both fast and slow muscle nerves. Compared with other groups, the percentage of type I fibers in the peroneus longus increased significantly in the group of rats with the pressure on the nerve and removal of the sarcolemma. The maximal contraction and relaxation time at the single twitch and complete tetanus of the peroneus longus were also increased. CONCLUSIONS: Our results show that pressing dominant nerves alter the skeletal muscle fiber types of the peroneus longus, which lead to increased maximal contraction and relaxation time, and significantly improve the ability in resistance to fatigue in rats. This study provides a basis for future clinical studies for external anal sphincter reconstruction using gracilis grafts that are doubly innervated by pressing on its dominant nerve.